Chapter 6 - epigenetics and disease

Epigenetics

• are chemical modifications of DNE sequences that alter the expression of genes resulting in disease and phenotypic variations

types of epigenetics modification

• DNA methylation

• Histone modification

• Microribonucleic acids (MIRNASO

DNA methylation

• is the attachment of a methyl group to a cytosine base that is followed by a guanine base

• AKA CPG Dinucleotide

• Causes a gene to become transcriptionally inactive or silent

• Key component of x-inactivation

Oncomir

• an MIRNA that stimulates cancer development and progression

• Acts as either an oncogene or tumor-suppressor gene

What do NCRNAS do?

• regulate gene expression

How do NCRNAS regulate gene expression?

• RNA interference

• Gene cosuppression

• Gene silencing

• Imprinting

• DNA demethylation

What are MIRNAS?

• are short nucleotides derived from introns of protein coding genes

Embryonic stem cells

• become any cell that is needed for development

• Totipotent

Key events in early embryogenesis

• differential epigenetics modification of specific DNA nucleotide sequences

  • Ensures that specific genes are expressed only in the cells and tissue types in which their gene productions are needed

• Helps determine the fate of each cell - that is the type of cell it becomes, such as myocyte, neuron, or fibroblast

genomic imprinting

• the process of gene silencing in which genes are predictably silenced, depending on which parent transmits them

Transcriptionally silenced genes - imprinted

• are usually heavily methylated

Diseases from abnormal imprinting patterns

• Prader-willi and angelman syndromes

• Beckwith-Wiedemann syndrome

• Russell-silver syndrome

Prader-Willi Syndrome

• is the deletion of approximately 4 million base (MB) pairs of the long arm of chromosome 15

• Inherited from FATHER

Clinical Manifestations - Prader-Willi Syndrome

• short stature

• Hypotonia - floppy babby

• Smalls hands and feet

• Obesity - constantly hungry could eat themselves to death

• Mild-to-moderate mental retardation

• Hypogonadism

Angelman syndrome

• has the same deletion of approximately 4 MB pairs of the long arm of chromosome 15

• Inherited from the MOTHER

Clinical manifestations - angelman syndrome

• severe mental retardation

• Seizures

• Ataxic gait

Pathophysiologic processes - Prader-Willi syndrome

• several genes in the critical region are transcribed only on the chromosome transmitted by father

• A paternally transmitted deletion removes the only active copies of these genes, producing the features of this syndrome

Pathophysiologic process - angelman syndrome

• genes encode a ligament for protein degradation during brain development thus resulting in mental retardation and ataxia

• In brain tissue genes are active only on the chromosome inherited from mother - maternally transmitted deletion removes the single active copy

Beckwith-wiedemann syndrome

• an overgrowth condition accompanied by an increased predisposition to cancer

• Usually identifiable at birth

• Presents an increased risk of developing Wilma tumor or hepatoblastoma

Beckwith-wiedemann syndrome - inheritance

• 2 copies of a chromosome form the father and no copy of the chromosome from the mother

• Uniparental

• Several genes on the short arm of chromosome 11 are imprinted on either the paternally or maternally transmitted chromosome disomy, affecting chromosome 11

DMR1 - normal

• gene that encodes insulin-like growth factor 2 (IGF2)

• Inactive on the maternally transmitted chromes but is active on the paternally transmitted chromosome

• Normal individual has 1 copy in IGF2

DMR1 - abnormal

• 2 copies of the paternally chromosome are inherited or the imprint it lost on the maternal copy of the IGF2 gene

• Active IGF2 gene is double dosed, producing increased levels of IGF2 during fetal development

Russell-silver syndrome

• causes the downregulation of IGF2 resulting in diminished growth

growth retardation

• proportionate short stature

• Leg-length discrepancy

• Small, triangular shaped face

What is the pathophysologic process occurring in a person with beckwith-wiedemann syndrome?

• extra copies of active IGF2

Fragile X Syndrome

• genetic and epigenetic factors

• FMR1

• FXTAS

FMR1

• CG repeats

  • Ovarian insufficiency

  • Early menopause

FXTAS

• late onset intention tremor

Which statement by the nurse indicates an accurate understanding of epigenetics and cancer?

• hypomethylation increases as tumors progress from benign neoplasms to malignancy

Prader - willi syndrome is an example of

• imprinting

What type of disease is prader - willi syndrome considered to be?

• following a liability of threshold model

What is a common characteristic of beckwith-wiedeman syndrome

• omphalocele - intestine outside the body

If an infant has beckwith-wiedemann syndrome they are at an increased risk for …

• Wilms tumor